Post-diagnosis Survival Research Articles

Indications and Efficacy of Gamma Knife Stereotactic Radiosurgery for Recurrent Glioblastoma: 2 Decades of Institutional Experience.

The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear. To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma. We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival. One hundred seventy-four glioblastoma patients (median age, 54.1years) underwent SRS a median of 8.7months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0cm 3 (range, 0.3-39.0cm 3 ) and 16.0Gy (range, 10-22Gy), respectively. Median overall survival was 10.6months after SRS and 19.1months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4cm 3 ; P = .009). Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect.

Factors Affecting Adjuvant Therapy in Stage III Pancreatic Cancer-Analysis of the National Cancer Database.

Background:Adjuvant therapy after curative resection is associated with survival benefit in stage III pancreatic cancer. We analyzed the factors affecting the outcome of adjuvant therapy in stage III pancreatic cancer and compared overall survival with different modalities of adjuvant treatment.Methods:This is a retrospective study of patients with stage III pancreatic cancer listed in the National Cancer Database (NCDB) who were diagnosed between 2004 and 2012. Patients were stratified based on adjuvant therapy they received. Unadjusted Kaplan-Meier and multivariable Cox regression analysis were performed.Results:We analyzed a cohort included 1731 patients who were recipients of adjuvant therapy for stage III pancreatic cancer within the limits of our database. Patients who received adjuvant chemoradiation had the longest postdiagnosis survival time, followed by patients who received adjuvant chemotherapy, and finally patients who received no adjuvant therapy. On multivariate analysis, advancing age and patients with Medicaid had worse survival, whereas Spanish origin and lower Charlson comorbidity score had better survival.Conclusions:Our study is the largest trial using the NCDB addressing the effects of adjuvant therapy specifically in stage III pancreatic cancer. Within the limits of our study, survival benefit with adjuvant therapy was more apparent with longer duration from date of diagnosis.

Pancreatectomy is underused in NSW regions with low institutional surgical volumes: a population data linkage study.

To examine differences in the proportions of people diagnosed with pancreatic cancer who underwent pancreatectomy, post-operative outcomes and 5-year survival in different New South Wales administrative health regions of residence. Retrospective analysis of NSW data on pancreatic cancer incidence and surgery, 2005-2013. The proportion of newly diagnosed patients with pancreatic cancer who were resected in each region; 90-day post-operative mortality; one-year post-operative survival; 5-year post-diagnosis survival. 14% of people diagnosed with pancreatic cancer during 2010-2013 (431 of 3064) underwent pancreatectomy, an average of 108 resections per year. After adjusting for age, sex and comorbidities, the proportion that underwent resection varied significantly between regions, ranging between 8% and 21% (P<0.001). Higher resection rates were not associated with higher post-operative 90-day mortality or lower one-year survival (unadjusted and risk-adjusted analyses). Higher resection rates were associated with higher 5-year post-diagnosis survival: the mean survival in regions with resection rates below 10% was 3.4%, compared with 7.2% in regions with rates greater than 15% (unadjusted and adjusted survival analyses; P<0.001). There was a positive association between regional resection rate and the pancreatectomy volume of hospitals during 2005-2009. An additional 32 people would be resected annually if resection rates in low rate regions were increased to the 80th percentile regional resection rate (18%). There is significant geographic variation in the proportion of people with pancreatic cancer undergoing pancreatectomy, and the 5-year survival rate is higher in regions where this proportion is higher.

Natural History of Untreated Hepatocellular Carcinoma in a US Cohort and the Role of Cancer Surveillance.

Determining the natural history and predictors of survival in patients with untreated hepatocellular carcinoma (HCC) in the United States is useful to test existing tumor classifications, identify subgroups of patients likely to benefit from treatment, and estimate lead time related to HCC surveillance. We identified a national cohort of 518 veterans diagnosed with HCC from 2004 through 2011, with follow-up ending in 2014, who received no palliative or curative treatment. We examined the association between postdiagnosis survival and patient factors, tumor characteristics, and prediagnosis surveillance. The mean age at HCC diagnosis was 65.7 years and most patients had hepatitis C (60.6%). Almost all patients (99%) died within the observation period; the median overall survival time was 3.6 months and survival times were 13.4, 9.5, 3.4, and 1.6 months for patients of Barcelona Clinic Liver Cancer stages 0/A, B, C, and D, respectively. In addition, model for end-stage liver disease and levels of α-fetoprotein were predictive of survival. Nearly 28% received prediagnosis HCC surveillance, which was associated with detection of disease at an earlier stage (Barcelona Clinic Liver Cancer 0/A/B; 26.4% vs 14.4%; P= .0006) and slightly longer survival than patients with no surveillance overall (5.2 months vs 3.4 months; P= .021); there was no difference in survival times of patients with 0/A stage who did versus did not receive surveillance (10.3 months vs 10.5 months). Patients with HCCs, including those detected through surveillance, survived for short time periods in the absence of treatment, irrespective of their initial stage at diagnosis. Model for end-stage liver disease scores and levels of α-fetoprotein were prognostic factors, independent of Barcelona Clinic Liver Cancer stage. The lead time related to detection by surveillance was modest (<2 months) and therefore unlikely to explain the survival benefit associated with surveillance in previous studies.

Reduction of estradiol in human malignant pleural mesothelioma tissues may prevent tumour growth, as implied by in in-vivo and in-vitro models.

This study aimed to investigate intratumoural estradiol and estrogen-receptors (ERα, ERβ and GPR30) in malignant pleural mesothelioma (MPM) to understand their function. Here, we report that immunohistochemistry of estradiol showed cytoplasmatic staining in 95% of fifty-seven human MPM samples with a trend toward a negative correlation between estradiol levels and the median post-diagnosis survival time. ERβ was only focally positive in 5.3% of cases, GPR30 and ERα were negative in our cases of MPM. GPR30 was detected mainly in glycosylated form in MPM cells. Moreover, G15, a GPR30 antagonist, induced MPM cell death. Altogether, these data suggest that MPM cells produce E2 interact with glycosylated forms of GPR30, and this facilitates tumour growth. Estradiol was found in MPM cells and plasma from mice mesothelioma xenografts. Concurrent reduction in tumour mass and plasmatic estradiol levels were observed in the mice treated with exemestane, suggesting that the reduction of E2 levels inhibit MPM growth. Thus, it appears that agents reducing estradiol levels could be useful to MPM therapy.

Palliative Chemotherapy Affects Aggressiveness of End-of-Life Care.

Although palliative chemotherapy during end-of-life care is used for relief of symptoms in patients with metastatic cancer, chemotherapy may lead to more aggressive end-of-life care and less use of hospice service. This is a population-based study of the association between palliative chemotherapy and aggressiveness of end-of-life care. Using the National Health Insurance Research Database of Taiwan, we identified 49,920 patients with metastatic cancer who underwent palliative chemotherapy from January 1, 2009, to December 31, 2011. Patients who received chemotherapy 2-6 months before death were included. Aggressiveness of end-of-life care was examined by previously reported indicators. Cardiopulmonary resuscitation and endotracheal tube intubation were included as indicators of aggressive end-of-life care. The association between palliative chemotherapy and hospice care was studied. Palliative chemotherapy was associated with more aggressive treatment. After adjustment for patient age, sex, Charlson Comorbidity Index score, cancer group, primary physician's specialty, postdiagnosis survival, hospital characteristics, hospital caseload, urbanization, and geographic regions, more than one emergency room visit (p < .001), more than one intensive care unit admission (p < .001), and endotracheal intubation (p = .02) during end-of-life care were significantly more common in patients receiving palliative chemotherapy. Patients who did not receive palliative chemotherapy received more hospice care in the last 6 months of life (p < .001). Although the decision to initiate palliative chemotherapy was made several months before death, this study showed that palliative chemotherapy was associated with more aggressive end-of-life care, including more emergency room visits and intensive care unit admissions, and endotracheal intubation. The patients who received palliative chemotherapy received less hospice service toward the end of life. Palliative chemotherapy is used for patients with incurable cancer toward the end of life (EOL). Aggressiveness of EOL care and hospice care are related to the quality of life of these patients. This study of data from the Taiwanese National Health Insurance Research Database found that palliative chemotherapy led to more aggressive EOL care and less hospice care. There is a need to provide patients with terminal cancer access to care information that best meets their needs, especially those patients who receive palliative chemotherapy.

Impact of precancer multimorbidity clusters on survival and functional outcomes after cancer in older patients.

291 Background: While multimorbidity clustering is a significant problem in older adults, the impact of clusters present prior to cancer on post-diagnosis survival and function is unknown. We used SEER-Medicare Health Outcomes Survey data for 4583 cancer patients to address this research gap. Methods: Patients with prostate (1741), breast (BC: 1345), colorectal (CRC: 904) and lung (593) cancer with pre- and post-diagnosis survey data were included. Surveys assessed comorbidity and activities of daily living (ADLs). Previously defined multimorbidity clusters were cardiovascular disease (CVD), skeletal, metabolic, pulmonary + major depressive disorder (MDD), and gastrointestinal (GI) + MDD. Cox regression models estimated hazard ratios (HR) for death after cancer diagnosis. Among those without pre-cancer ADL impairment, modified Poisson regression models estimated relative risk (RR) for developing post-cancer functional impairment (ADL ≤ 4). Models controlled for age, race, education, poverty level, stage, and treatment (radiation, surgery). Results: Median age at cancer diagnosis was 74y (65-103). Post-diagnosis mortality: After 6y median follow-up, mortality was 30%; 5y survival was 74%.Prostate, BC and CRC patients with pre-diagnosis CVD clusters were at increased risk of death compared to those without CVD cluster (HR 1.9, 2.0, 1.7, respectively, p &lt; 0.05). Compared to those without the cluster, prostate and BC patients with metabolic cluster were at increased risk (HR 1.7, 1.9, respectively, p &lt; 0.05) and prostate cancer patients with pulmonary conditions + MDD or GI + MDD (HR 1.9, 2.1, respectively, p &lt; 0.05) were at increased risk. Post-diagnosis functional impairment: Prevalence of moderate functional impairment at a median of 1y after cancer diagnosis was 31%. Prostate, lung, and CRC survivors with GI + MDD had a significant RR of developing impairment (RR 1.8, 1.8, and 1.7, p &lt; 0.001). For BC patients, those with skeletal cluster had a 2.1 RR (p &lt; 0.001). Conclusions: Specific multimorbidity clusters prior to cancer are associated with post-cancer mortality and ADL impairment and identify at-risk groups where interventions can be instituted to decrease morbidity and mortality.

Kinetics of postdiagnosis platelet count with overall survival of pancreatic cancer: a counting process approach.

The association between long‐term variation of postdiagnosis platelets and survival of pancreatic cancer (PC) has never been discussed by using dynamic survival analysis method. In this retrospective study, we analyzed 311 histologically confirmed PC patients identified from a mega population‐based electronic inpatients database from 2012 to 2013 in China. Counting process approach was applied to restructure the original survival data, the association between post‐diagnosis platelet count and overall survival (OS) of PC was evaluated by multiple failure‐time Cox proportional hazards model. After counting process adjustment, multiple failure‐time Cox proportional hazards model revealed that, regardless of the treatment modalities PC patients received, postdiagnosis thrombocytopenia was prominently associated with OS, compared with PC patients with normally ranged platelet count, the HRs ranged from 2.04 (95% CI: 1.14–3.67) to 10.82 (95% CI: 2.63–44.54), and this inverse association was robust based on further sensitivity analysis. On the contrary, the association between thrombocytosis and OS of PC tended to be inconclusive. Our findings suggested that postdiagnosis thrombocytopenia was associated with significantly compromised survival among PC patients from this large retrospective cohort. Underlying mechanisms behind this association should be further investigated.

Effective and cancer-specific siRNA delivery to human hepatocellular carcinoma cells mediated by poly(beta-amino ester) nanoparticles.

Event Abstract Back to Event Effective and cancer-specific siRNA delivery to human hepatocellular carcinoma cells mediated by poly(beta-amino ester) nanoparticles. Camila Zamboni1, 2, Kristen K. Kozielski1, Nicholas Radant1, Luke J. Higgins3, Martin G. Pomper4 and Jordan J. Green1, 5, 6 1 Johns Hopkins University School of Medicine, Biomedical Engineering, United States 2 Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, Brazil 3 Stanford, Radiology, United States 4 Johns Hopkins Medical Institutions, Russell H. Morgan Department of Radiology and Radiological Science, United States 5 Johns Hopkins University School of Medicine, Department of Material Science and Engineering, United States 6 Johns Hopkins University School of Medicine, Neurosurgery and Ophthalmology, United States Introduction: Liver cancer is the second leading cause of cancer mortality worldwide. Hepatocellular carcinoma (HCC) accounts for approximately 90%[1] of primary liver cancers and has a five year post-diagnosis survival rate of only 12%[2],[3]. Limited efficacy of the current treatment options is one of the most challenging problems existing in the field of liver oncology. Gene therapy offers promising advantages that might overcome these limitations. Unfortunately, the poor selectivity in vector targeting still represents a main obstacle in gene therapy. Here we demonstrate that bioreducible poly(beta-amino ester)s (PBAEs) nanoparticles suggest an effective and cancer-specific siRNA delivery strategy to target human HCC cells. Materials and Methods: A human liver epithelial cell line (THLE-3) and a human hepatocellular carcinoma cell line (HepG2) were separately cultured and treated with nanoparticles formed by PBAEs and either AllStars Hs Cell Death siRNA (death siRNA) or AllStars Negative Control siRNA (Qiagen, Netherlands). While the death siRNA consists of a blend of siRNAs that silence important genes related to cell survival, the negative control has no target within mammalian cells. Effective delivery of death siRNA leads to cell death and the negative control allows evaluation of non-specific cell toxicity. Two bioreducible PBAEs, that we synthesized and evaluated at five different concentrations, were used as vectors to carry either death siRNA or negative control siRNA. Three days post-treatment, DAPI/PI staining was applied to differentiate live from dead cells. Live cells were counted using the ImageJ software. Results and Discussion: Our bioreducible PBAE nanoparticles lead to effective siRNA delivery and concomitant siRNA-mediated cell death to the human HCC cell line. The bioreducible polymer R646 (Figure 1), at 270ng/ul was considered to form the favorite formulation. A siRNA-mediated cell death of 89.1 ± 5% for HepG2 and 30.2 ± 16% for THLE-3 cells were observed, with a statistically significant difference between the HCC cells when compared to the healthy hepatocytes (p<0.05). Non-specific toxicity to healthy hepatocytes remained below 26.1 ± 6%. Conclusion: Bioreducible poly(beta-amino ester)s nanoparticles not only seem to provide high siRNA-mediated death to HCC cells but also enable cancer-target in vitro. Even though further validation in vitro and in vivo is required, these findings suggest that biomaterial mediated siRNA delivery using bioreducible poly(beta-amino ester)s is a potentially viable strategy for liver cancer treatment.

Factors Influencing Graft Outcomes Following Diagnosis of Polyomavirus -Associated Nephropathy after Renal Transplantation.

BackgroundPolyomavirus associated nephropathy (PVAN) is a significant cause of early allograft loss and the course is difficult to predict. The aim of this study is to identify factors influencing outcome for PVAN.MethodsBetween 2006 and 2014, we diagnosed PVAN in 48 (7.8%) of 615 patients monitored for BK virus every 1–4 weeks after modification of maintenance immunosuppression. Logistic or Cox regression analysis were performed to determine which risk factors independently affected clinical outcome and graft loss respectively.ResultsAfter 32.1±26.4 months follow-up, the frequencies of any graft functional decline at 1 year post-diagnosis, graft loss and any graft functional decline at the last available follow-up were 27.1% (13/48), 25.0% (12/48), and 33.3% (16/48), respectively. The 1, 3, 5 year graft survival rates were 100%, 80.5% and 69.1%, respectively. The mean level of serum creatinine at 1 year post-diagnosis and long-term graft survival rates were the worst in class C (p<0.05). Thirty-eight of 46 (82.6%) BKV DNAuria patients reduced viral load by 90% with a median time of 2.75 months (range, 0.25–34.0 months) and showed better graft survival rates than the 8 patients (17.4%) without viral load reduction (p<0.001). Multivariate logistic regression analysis showed that extensive interstitial inflammation (OR 20.2, p = 0.042) and delayed fall in urinary viral load (>2.75 months for >90% decrease) in urine (OR 16.7, p = 0.055) correlated with worse creatinine at 1 year post-diagnosis. Multivariate Cox regression analysis showed that extensive interstitial inflammation (HR 46988, p = 0.032) at diagnosis, and high PVAN stage (HR 162.2, p = 0.021) were associated with worse long-term graft survival rates.ConclusionsThe extent of interstitial inflammation influences short and long-term graft outcomes in patients with PVAN. The degree of PVAN, rate of reduction in viral load, and viral clearance also can be used as prognostic markers in PVAN.

Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype.

Adiposity has been linked with increased breast cancer risk and mortality. It is established that etiologic associations for adiposity vary by tumor subtype, but the influence of adiposity on subtype-specific survival is unknown. Study participants were 1,109 invasive breast cancer participants in the population-based Carolina Breast Cancer Study, diagnosed between 1993 and 2001, and with tissue blocks available for immunohistochemical subtyping. General and central adiposities were assessed by body mass index (BMI) and waist-to-hip ratio (WHR), respectively, based on in-person measurements after diagnosis. Vital status as of 2011 was determined using the National Death Index (median follow-up = 13.5 years). Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer (BC)-specific and all-cause mortalities. Among all patients, high WHR (≥0.84), but not BMI, was associated with all-cause mortality (adjusted HR 1.50, 95% CI 1.11-2.05, <0.77 as reference). No significant association between adiposity and BC-specific mortality was detected, although there was a suggestion of increased mortality risk among high-BMI (≥30 kg/m(2)) patients with basal-like tumors (adjusted HR 2.44, 95% CI 0.97-6.12, <25 kg/m(2) as reference). Quantitative differences in all-cause mortality were observed by subtype, with BMI associated with basal-like mortality and WHR associated with luminal mortality. The associations were attenuated by tumor characteristics. Our study confirms the association of adiposity and unfavorable overall survival in breast cancer patients and suggests that this association may vary by intrinsic subtype and adiposity measure.

Abstract 44: EGFR and Dock180 activate MLK3 to drive invasion of glioblastoma cells

Abstract Glioblastoma (GBM) is the most common and deadly form of brain tumor in adults, with an average post-diagnosis survival time of 15 months. While GBMs rarely metastasize to distant organs, they readily invade into surrounding brain tissue, leading to incomplete surgical resection and subsequent tumor recurrence. Epidermal Growth Factor Receptor (EGFR) signaling is aberrantly activated in a majority of GBM tumors, and is clearly implicated in multiple malignant phenotypes, including migration and invasion. However, direct targeting of EGFR has been largely unsuccessful, for multiple reasons, including compensatory upregulation of other RTKs. Thus, identifying and targeting key signaling nodes that are downstream of multiple RTKs is of therapeutic importance. Several guanine nucleotide exchange factors (GEFs), including Dock180, a Rac1 GEF, are implicated in GBM invasion through activation of small GTPases, Rac and Cdc42. The Mixed Lineage Kinases (MLKs) are a family of cytosolic MAP3Ks that activate multiple MAPK pathways, including the c-Jun N-terminal kinase (JNK), ERK, and p38 pathways. MLK3 is activated through the binding of activated, GTP-bound Rac and/or Cdc42 to induce dimerization and activation. Herein, the role of MLK signaling on GBM cell migration is investigated using an ATP-competitive pan-MLK inhibitor (previously in phase II/III clinical trials for Parkinson's disease), as well as siRNA targeting MLK3. Data from this study demonstrate that both MLK inhibition and silencing of MLK3 dramatically reduce the migration and invasion of GBM cells. EGF-induced activation of JNK in multiple GBM cell lines is blocked by a pan-MLK inhibitor, as well as an MLK3-specific siRNA. Furthermore, the MLK inhibitor blocks EGF-induced migration in a 2D wound healing assay. Mutant EGFRvIII-induced JNK activation is blocked by MLK inhibition, and invasion of primary GBM6 cells (express EGFRvIII) is blocked in a 3D invasion assay. Dock180, a Rac GEF has been shown to be critical for multiple malignant phenotypes in GBM cells, including migration and invasion. Based upon Drosophila genetics, the Dock180 homolog (MBC), a Rac GEF, acts upstream of Rac, the MLK homolog (slipper) and JNK. Therefore we hypothesized that Dock180 might be an upstream activator of MLK3. Our data demonstrate that Dock180 complexes with MLK3, and that ectopic expression of Dock180 activates MLK3 activation in a Rac-dependent manner. Furthermore, siRNA-mediated silencing of Dock 180 and of MLK3 reduce EGF-induced JNK activation to similar extents, consistent with the idea that they act in the same signaling axis leading to JNK activation. Finally, ectopic expression of MLK3 (which leads to its auto-activation) is sufficient to rescue the defect in migration due to Dock180 silencing. Based upon these data, we propose that an EGFR-Dock180-Rac-MLK-JNK signaling axis drives GBM migration and 3D invasion, and that targeting MLKs may be a useful therapeutic approach for treating patients with GBM. Citation Format: Sean A. Misek, Jian Chen, Kathleen A. Gallo. EGFR and Dock180 activate MLK3 to drive invasion of glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 44. doi:10.1158/1538-7445.AM2015-44

Retraction Note to: The 'obesity paradox' and survival after colorectal cancer: true or false?

Body mass index (BMI), as an approximation of general adiposity, is an established risk factor for incidence of several adult cancer types, including colorectal cancer (CRC). There is a common perception that these relationships extrapolate directly as adverse prognostic factors after diagnosis, but evidence for this is lacking. The paper from Sclesinger et al. in this issue of the journal adds a new dimension to this debate focusing on relationships of post-diagnosis BMI (as a marker of the steady-state weight among survivors) and survival, and provides evidence on a decreased mortality risk among overweight (post-diagnosis BMI 25.0–29.9 kg/m2) compared with normal weight (post-diagnosis BMI 18.5–24.9 kg/m2) CRC survivors—an example of an ‘obesity paradox.’ The observation of the ‘obesity paradox’ is well documented in the methodology literature, but perhaps, less familiar to the cancer readership. Three broad classes of explanation are posited: (1) the associations are true and plausible; (2) the associations are false and reflect methodological issues; or (3) the observations represent a specific form of selection bias, known as collider bias. The present author argues that the obesity paradox reflects the latter—a product of a statistical bias—and emphasizes that, while these findings are hypothesis generating, they will not alter clinical practice or recommendations.

Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients.

Background:Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence.Methods:The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression.Results:A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001).Conclusions:Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.

Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype

Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype

Determinants for aggressive end-of-life care for oral cancer patients: a population-based study in an Asian country.

Few studies have addressed the association between oral cancer and end-of-life (EOL) aggressive care using population data. We investigated the relationship between patient demographics, primary physician's specialty, and hospital characteristics of patients who died from oral cancer in Taiwan from 2009 to 2011 and the aggressiveness of their EOL care.This nationwide population-based, retrospective cohort study identified 5386 patients who died from oral cancer identified from Taiwan's National Register of Deaths Database and collected their claims data from Taiwan's National Health Insurance Research Database. Accepted indicators of aggressiveness of EOL care were examined using a composite measure adapted from Earle et al. Scores ranged from 0 to 6; the higher the score, the more aggressive the EOL care. The impact of each variable on the aggressiveness of EOL care was examined by multivariate analysis using a random-intercept model.The mean composite score for aggressiveness of EOL care was 2.68 ± 1.37. Oral cancer patients who were younger, had a higher level of comorbidity or metastasis, belonged to a lower-level individual socioeconomic status, were cared for by nononcologists, had longer postdiagnosis survival times, or resided in urban areas were more likely to receive aggressive care at EOL. Compared with previous studies, oral cancer patients near death in this nationwide study had a far higher utilization rate (>50%) of chemotherapy, emergency room services, and intensive care unit services.Our findings indicate that oral cancer patients receive extensive aggressive medical care at EOL. Future research may be needed to examine the effect of the means (indicators) of aggressive treatment on survival, quality of life, and medical costs, especially since current research suggests such care may adversely affect quality of life and important preparation of death in these patients.

Multiple Myeloma in the Afro-Caribbean Inner City Population: Conventional Cytogenetics and Survival

Background:Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States. African Americans have among the highest risks of MM and MGUS with several distinct features compared to existing literature. Furthermore, the prevalence of MM is even higher in the Afro-Caribbean population. Cytogenetic and molecular genetic abnormalities predict outcome in patients with MM. Hyperdiploid MM (H-MM) generally has a better prognosis than nonhyperdiploid MM (NH-MM). In addition, patients with additional chromosome 1 abnormalities, loss of chromosome 13, translocation t(14;16) and t(4;14) tend to have a worse survival while patients with translocations t(11;14) are associated with improved survival. In our patient population, the most common cytogenetic abnormalities and their effect on survival remain unknown.Objective:This study was performed to establish a profile of Afro-Caribbean patients with newly diagnosed Multiple Myeloma in order to gain further insight into unique cytogenetic abnormalities and their effects on survival.Methods:Patients with Multiple Myeloma at Kings County Hospital Center and University Hospital at Brooklyn from 2000-2013 were identified by our tumor registries (n=311). We included all the newly diagnosed patients from 2000-2013 who underwent a bone marrow biopsy and conventional cytogenetic by chromosome banding and FISH (n= 173). Patients who did not have a cytogenetic analysis were excluded. Data was collected at the time of initial presentation to include demographics and cytogenetic abnormalities. Survival data was obtained from Social Security Death Index. Differences in frequency of each cytogenetic abnormality by mortality status were examined using Chi-Square or Fisher’s Exact Tests. Two sets of age-adjusted logistic regression models were used to examine potential cytogenetic correlates of both poor (less than two years) and good (4 years or more) survival. Data analysis was performed using SPSS Advanced Statistics.Results:The median age at the time of diagnosis was 65 (Range 36-90). Chromosome banding and FISH showed abnormal cytogenetics in 46% of our patients (n=79). These patients were also found to have multiple abnormal clones. NH-MM was found in 24% (n=19) and H-MM was found in 39% (n=31) of the 79 patients. The most commonly affected abnormalities were trisomiesof odd-numbered chromosomes; +1 (47%), +3 (19%), +5 (21%), +7 (24%), +9 (47%), +11 (42%), +15 (44%), +17 (9%) and +19 (29%).Thirty five percent of 173 patients have expired (n=60). The median survival in the deceased patients was 6.2 years (Range 0.34-12.9). When we examined all patients who lived greater than four years post-diagnosis (n=152), we found significant abnormalities including +5 (p=0.052), NH-MM (p=0.009) and t(11;14) (p=0.03) (See Table 1). Indicators of poor prognosis including 1q gain (p=0.13), loss of chromosome 13 (p=0.21) and del17 (p=0.08) were not significant. In patients who are living, 19% (n=29) have not yet reached the four-year post-diagnosis survival. Less than ten percent underwent autologous stem cell transplantation.Excludes patients who lived less than 3 months post diagnosis August 5 2014Table 1:Age-Adjusted Logistic Regression Models Predicting Good Survival (lived 4 years or more post-diagnosis)Chromosome abnormality ( + gain, - loss)Age-Adjusted Odds Ratio (95% CI) N=152P-value1+0.77 (0.26, 2.29)0.631-2.91 (0.58, 14.57)0.193+1.05 (0.35, 3.17)0.935+0.47 (0.22, 1.00)0.0527+0.39 (0.14, 1.10)0.0811+0.80 (0.36, 1.75)0.5714+2.07 (0.62, 6.91)0.2415+0.74 (0.34,1.60)0.4419+1.20 (0.46, 3.13)0.71X-0.42 (0.11, 1.50)0.18Y-0.40 (0.13, 1.26)0.12Hyperdiploidy0.88 (0.39, 2.00)0.88Nonhyperdiplody0.24 (0.08, 0.70)0.009t(4;14)0.76 (0.27, 2.15)0.60t(11;14)0.18 (0.04, 0.86)0.03Conclusion:In this group of Afro-Caribbean patients, median survival (6 years) was higher than Surveillance, Epidemiology, and End Results (SEER) data and more recent review of literature. Gain of chromosome 5 and t(11;14) are consistent with existing data for good prognosis. However, NH-MM which is usually an indicator of poor prognosis was also highly significant in the four-year post-diagnosis survival. This further supports the notion that prognostic value of cytogenetic analysis in this population requires further exploration. DisclosuresNo relevant conflicts of interest to declare.

Lethal migration: the bradykinin story.

Lethal migration: the bradykinin story.

Abstract 3398: Reciprocal regulation of MYB and CXCR4 in pancreatic cancer cells: Potential pathobiological implications

Abstract Pancreatic cancer remains one of the most lethal malignancies with a median post-diagnosis survival of 3-8 months, and a 5 year survival of ∼6%. The poor outcome from pancreatic cancer is largely due to the presence of locally advanced or metastatic disease at the time of diagnosis. Therefore, it is imperative to identify novel molecular targets driving aggressive and metastatic progression of pancreatic cancer, and build up a better understanding of the underlying molecular mechanisms. In this regard, we have identified that MYB, encoding for an oncogenic transcription factor (a cellular progenitor of v-Myb oncogenes), is overexpressed in majority of pancreatic cancer cases and cell lines. Furthermore, our data from gain and loss of function studies (in BxPC3 and MiaPaCa cells, respectively) show that MYB overexpression is associated with pancreatic tumor growth and metastasis. From the mechanistic standpoint, we observe that MYB regulates the expression of CXCR4 through direct binding to its promoter. MYB-overexpressing BxPC3 cells exhibit significantly enhanced migration and invasion against a CXCL12 (sole ligand for CXCR4) gradient, whereas it is suppressed in MYB-silenced MiaPaCa cells as compared to their respective control cells. Furthermore, MYB-overexpressing cells exhibit greater resistance to serum-deprivation in CXCL12-supplemeted media, an effect that is abrogated upon CXCR4 silencing. Interestingly, in parallel studies, we have observed that treatment with CXCL12 also leads to MYB upregulation in pancreatic cancer cells in a CXCR4 dependent manner. Together, these data are suggestive of a novel positive feedback regulatory loop between CXCR4 and MYB and hold important significance for pancreatic cancer pathobiology. Citation Format: Sanjeev K. Srivastava, Arun Bhardwaj, Sumit Arora, Seema Singh, William E. Grizzle, Ajay P. Singh. Reciprocal regulation of MYB and CXCR4 in pancreatic cancer cells: Potential pathobiological implications. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3398. doi:10.1158/1538-7445.AM2014-3398

The 'obesity paradox' and survival after colorectal cancer: true or false?

Body mass index (BMI), as an approximation of general adiposity, is an established risk factor for incidence of several adult cancer types, including colorectal cancer (CRC). There is a common perception that these relationships extrapolate directly as adverse prognostic factors after diagnosis, but evidence for this is lacking. The paper from Sclesinger et al. in this issue of the journal adds a new dimension to this debate focusing on relationships of post-diagnosis BMI (as a marker of the steady-state weight among survivors) and survival, and provides evidence on a decreased mortality risk among overweight (post-diagnosis BMI 25.0-29.9 kg/m(2)) compared with normal weight (post-diagnosis BMI 18.5-24.9 kg/m(2)) CRC survivors-an example of an 'obesity paradox.' The observation of the 'obesity paradox' is well documented in the methodology literature, but perhaps, less familiar to the cancer readership. Three broad classes of explanation are posited: (1) the associations are true and plausible; (2) the associations are false and reflect methodological issues; or (3) the observations represent a specific form of selection bias, known as collider bias. The present author argues that the obesity paradox reflects the latter-a product of a statistical bias-and emphasizes that, while these findings are hypothesis generating, they will not alter clinical practice or recommendations.